TWI324934B - Pharmaceutical compositions for the treatment of asthma - Google Patents

Abstract

The invention relates to aerosolized formulations for the treatment of asthma that contain mometasone furoate and formoterol fumarate and processes for preparing same.

Description

1324934 A7 B7 V. INSTRUCTIONS (1) The present invention relates to an aerosol suspension formulation containing no fluorocarbon (CFC's). In particular, the present invention relates to formulations which are substantially free of CFC's and which have particular utility in medical applications, particularly inhalation devices (MDI's) for metered doses. Dosimetric inhalers have proven to be effective oral and transdermal delivery systems, which have been widely used to deliver bronchiectasis and steroids to asthmatic as well as other compounds such as pentamidine and non-bronchial dilatation. Anti-inflammatory drugs. The activity of the compound administered in this manner is rapidly initiated without any significant side effects, and has led to the formulation of a large number of compounds for administration via this route. Typically, the drug is delivered to the patient by a propellant system which generally comprises one or more propellants having an appropriate vapor pressure and suitable for oral or nasal administration. More propellant systems typically include CFC propellant 11, CFC propellant 12, CFC propellant 114, or mixtures thereof. The vapor pressure system of the propellant system is often adjusted by mixing lower volatility liquid excipients and propellants. However, propellants CFC 11, CFC 12 and CFC 114 are known as fluorocarbon-based compounds which are associated with ozone destruction in the atmosphere. It has been assumed that ozone can block certain harmful UV light and thus reduce the ozone content in the atmosphere, which will lead to an increase in the incidence of skin cancer. In the mid-1970s, certain steps were taken to reduce CFC emissions from aerosols. Other propellants such as hydrocarbons or products are also used for delivery in different ways. Due to the relatively low use rate of CFC for medical use, ie less than 1% of the total CFC shot, and because of the health benefits associated with metered dose inhalers, the use of CFC in metered dose inhalers has not been taken at this time. Propellant. -4- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm)

Binding

Line 1324934 A7 B7 V. INSTRUCTIONS (2) However, continuous and more sophisticated ozone measurements have shown early limits CFC usage is still insufficient and additional important steps are required to dramatically reduce CFC emissions. It has been recommended to actually interrupt CFC manufacturing. As a result, it is not possible to continue using CFC propellants in the medium and long term. While some efforts have utilized non-pressurized metered dose inhalers, many of these devices have not been fully successful. Some performance issues are related as follows: uniform dose delivery, mechanical complexity, aerosol requirements per unit of aerosol container, compatibility with strict regulatory standards, and patient use, especially when patients have acute medical needs Such devices are large and/or tiring and difficult to use for individuals. As a result, there is a need for a CFC-free pressurized aerosol formulation, such as a metered dose inhaler that is substantially free of CFC's. Non-CFC propellant systems are subject to several standards for pressurized metered dose inhalers. It must be non-toxic, stable and non-reactive with the pharmaceutical and other major components of the valve/driver. Other propellants found to be suitable are CF3CHFAF3, also known as HFA 227, HFC 227 or 1,1,1,2,3,3,3-heptafluoropropane. Hereinafter, this propellant will be referred to as HFA 227. However, certain physical properties of HFA 227, i.e., polarity and solubility, are different from conventional CFC propellants. Conventional surfactants are soluble in HFA 2 2 7 . Furthermore, when the drug is delivered as a solution, the drug is insoluble in the propellant. The difference in polarity between HFA 227 and the previously used CFC propellant can be difficult to deliver by replacing CFC propulsion timing with HFA 227. Pharmaceuticals in non-CFC propellants may emulsify, settle or coagulate, even if they do not occur in CFC propellants. Other non-gas fluorocarbon propellants are hydrofluorocarbon 134a, also known as 1,1,1,2-tetrafluoroethane or HFA 134a. Hereinafter, this propellant will be referred to as HFA 134a. -5- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm)

Binding

Line 1324934 A7 B7 V. INSTRUCTIONS (3) The formulation of the prior art contains mometasone and HFA 227 in combination with a metered dose inhaler which utilizes ethanol suspension of crystalline mometasone in combination with a propellant. These formulations have improved stability over the long term. The specific combinations described above do not provide the desired solubility, stability, low toxicity, exact dosage, correct particle size (if a suspension), and/or compatibility with the valve assembly conventionally used in metered dose inhalers. Accordingly, there remains a need for a formulation that does not contain CFC for the treatment of asthma and a method of making the same that does not have the aforementioned disadvantages. SUMMARY OF THE INVENTION Accordingly, the present invention is directed to a method of making a non-toxic formulation that is substantially free of CFC's and that has improved stability and pharmaceutically compatible properties and is relatively easy to manufacture. The invention also relates to a metered dose inhaler comprising an aerosol suspension formulation for inhalation, the aerosol suspension formulation for inhalation comprising: an effective amount of mometasone furoate; an effective amount of famot Alcohol fumarate; and 1,1,1,2,3,3,3-heptafluoropropane; wherein the ratio of mometasone furoate to faroterol fumarate is about 400 micrograms of mometasone The bismuth citrate is about 12 micrograms of famotote fumarate to about 50 micrograms of mometasone citrate to about 6 micrograms of famotote fumarate, which has a velvety coverage of mometasone citrate The farteol fumarate salt is (flocculate), and wherein the formulation is substantially free of a carrier. The invention further relates to a metered dose inhaler comprising an aerosol suspension formulation for inhalation, the aerosol suspension formulation for inhalation comprising: an effective amount of mometasone furoate; an effective amount of famot Alcohol fumarate; about -6- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1324934 A7 ________Β7 V. Invention description (""""4~)~ ' 0 05 % to about 3% by weight of bulkmg agent; and 1,1,12_ four gas acetyl; wherein the ratio of mometasone citrate to faroterol fumarate is about 400 Microgram of mometasone citrate versus about 12 micrograms of famotote fumarate to about 50 micrograms of mometasone citrate to about 6 micrograms of famotote fumaric acid, of which mometasone citrate The famotote fumarate is flocculated. The invention further relates to a method of making an aerosol suspension formulation for inhalation. The aerosol suspension formulation for inhalation comprises: an effective amount of mometasone furoate; an effective amount of famotol fumar Acid salt; and ^,1,2,3,3,3-heptafluoropropane; wherein the ratio of mometasone furoate to faroterol fumarate is about 400 micrograms of mometasone furoate 12 micrograms of famotote fumarate to about 50 micrograms of mometasone furoate to about 6 micrograms of famotote fumarate, and wherein the aerosol suspension formulation is rich in the famotol The carboxylate is covered with a molybdenite velvet, and wherein the formulation is substantially free of a swelling agent, the method comprising the steps of: micronizing mometasone citrate. and famot a dry powder blend of an alcohol fumarate is mixed with a dry powder surfactant to form a homogeneous mixture; the mixture is filled into a dose dose inhaler tank; the tank is covered with a metering valve roll; and in the tank Filling in a non-chlorofluorocarbon propellant ^ The invention is also related to a product prepared by the aforementioned method. The present invention also relates to a metered dose inhaler containing an aerosol suspension formulation for inhalation. The aerosol suspension formulation for inhalation comprises: an effective amount of mometasone citrate, an effective amount of a special alcohol fumarate; a dry powder surfactant; and 1,1,1,2,3,3,3-heptafluoropropane; wherein the Momei paper grade is applicable to the China National Standard (CNS) A4 specification ( 210X 297 mm) 1J24934

= the ratio of decanoate to farotropin fumarate is about 12 micrograms of famotote fumarate to about 2 micrograms of mometasone furoate For about 6 micrograms of famotote fumarate, wherein the famot is covered with molasses citrate in the form of a fumarate, and the formulation does not contain an external excipient, and wherein The metered dose inhaler can emit a dose having a uniform drug content when the metered dose inhaler is driven. Tian Ben, Ming (4) - a metered dose inhaler containing an aerosol suspension formulation for inhalation, the aerosol suspension formulation for inhalation comprising an effective amount of mometasone furoate; an effective amount Famotetan fumarate; and 1'1,1,2,3,3,3-heptafluoropropane; wherein the ratio of mometasone furoate to faroterol fumarate is about 400 micrograms It is about 12 micrograms of famotote fumarate to about 50 micrograms of mometasone furoate to about 6 micrograms of famotote fumarate, wherein the farmore alcohol is rich. The acid salt is covered with a melamine lintinate velvet and wherein the formulation contains less than 1% of the epoxide degradation products of mometasone decanoate. The invention further relates to a metered dose inhaler comprising an aerosol suspension formulation for inhalation. The aerosol suspension formulation for inhalation comprises: an effective amount of mometasone furoate; an effective amount of famot Alcohol fumarate; and 1,1,1,2,3,3,j-seven mice, wherein the ratio of mometasone furoate to faroterol fumarate is about 400 micrograms It is about 12 micrograms of famotote fumarate to about 50 micrograms of mometasone furoate to about 6 micrograms of famotote fumarate, wherein the farmore alcohol is rich. The acid salt is covered with a melamine lintinate velvet, wherein the metered dose inhaler is driven to dispense a fine particle percentage of from about 55% to about 85% and wherein the fine particle size is less than about 4 7 micron

Binding

-8 -

1324934 A7 B7 V. Description of invention (6) meters. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a three-unit average mometasone furoate containing HFA 227 and a fumarate fumarate/mometazolate 6/50 microgram drive combination without a swelling agent. Andersen cascades the contours. Figure 2 is a three-unit average of the famotol fumarate Andersen grade containing HFA 227 and a fumarate-free fumarate/mometazol bismuth ruthenate 6/50·microgram drive combination. Collision collision contour. Figure 3 is a three-unit average of the famotol fumarate Andersen cascade collision with HFA 134a and a small amount of bulking agent, famotote fumarate / mometasone citrate 6/50 microgram drive combination Rotation. Figure 4 is a three-unit average of memadzine citrate Andersen cascading collision profile with HFA 134a and a small amount of bulking agent, famotote fumarate/mometazidine citrate 6/50 microgram drive combination . DETAILED DESCRIPTION OF THE INVENTION Mometasone furpate is an active ingredient in ELOCON® lotions, creams and ointments and has the chemical name 9,2 1-dichloro-11(/3), 17-two Anti-inflammatory corticosterone of hydroxy-16(α)-methyl-pregn-1,4-diene-3,20-dione 17-(2-decanoate). In fact, it is insoluble in water; slightly soluble in methanol, ethanol and isopropanol; soluble in acetone and gas; and completely soluble in tetrahydrofuran. Its non-coordination coefficient between octanol and water is greater than 5,000. Mometol can exhibit various hydrated crystals and enantiomeric forms such as monohydrate. This product was obtained from Schering-Plough, Kenneth, New Jersey. Formoterol fumarate is a selective point 2-kid-9 - This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x 297 mm) 1324934 A7

The bronchodilator of the upper gland. Its chemical name is (士)·2_hydroxy_5 [(irs)_pyrazin-2-[[(lRS)-2-(4-methoxyphenyl)+methylethyl]amino]ethyl ] Amidoxime fumarate dihydrate. Famotetan fumarate is a white to yellow crystalline powder which has been reported to be completely soluble in glacial acetic acid, soluble in methanol, insoluble in ethanol and isopropanol, slightly soluble in water, and practically insoluble in acetone. , ethyl acetate and ethyl acetate. The farote alcohol fumarate can exhibit various hydrated crystals and later isomers such as monohydrate. This product was obtained from Novartis, East Hawa, New Jersey. This month's month is especially useful for the pharmaceuticals of famotote fumarate and mometasone or its final salts, enantiomers and clathrates. The weight ratio of the mometasone furoate and the faroterol fumarate may be about 1 to 1 of mometasone furoate to famotol fumarate, or about 5 〇 summer莫 美 冗 冗 对 对 对 对 对 对 对 对 对 对 对 法 法 对 法 法 对 对 对 对 对 对 对 对 对 对 对 对 对 对 对 对 对 对 对 对 对 对 法 法 对 对 对For famotote fumarate, or about 16 to 7 mometasone saccharate to faroterol fumarate, 4 about 1 GItl of mometasone saccharate to famotol Caprate, or about 8 tbl of mometasone (iv) salt versus faroterol fumarate. A proportional scoop is slightly equal to a dose range of 6 micrograms of famot ferulate fumarate to 50 micrograms of mometasone citrate per dose, or about 6 micrograms per dose versus 100 micrograms of famotol fumarate. For mometasone citrate, or about 8 micrograms per dose of gram microgram of farotropol fumarate versus mometasone saccharate' or about 6 micrograms per dose versus 200 micrograms of famotol Fumarate to mo-10-

V 1324934 A7 ---------------B7 V. INSTRUCTIONS (8) Methasone breaks the salt' or about 8 micrograms per dose to 200 micrograms of famotol fumaric acid Salt versus mometasone citrate, or about 12 micrograms per dose versus 200 micrograms of wolfmoate alcohol fumarate versus mometasone citrate, or about 12 micrograms per dose versus 400 micrograms of famot Alcohol fumarate versus mometasone citrate. I Technology: The pharmaceutical aerosol formulation, which is based on the propellant in the art, typically uses a mixture of liquid oxygen-gas carbon as a propellant, but many others use a single propellant. As is known in the art, the propellant acts as a carrier for both the active ingredient and the excipient. Fluorotrichloromethane, dichlorodifluoromethane and dichlorotetrafluoroethylene & are the most commonly used propellants in aerosol formulations for administration by inhalation. However, this fluorocarbon (CFC, s) is related to the destruction of the ozone layer and its manufacture is separated. HFA 134a & H.FA 227 can be said to be less harmful to ozone than many chlorofluorocarbon propellants, and their use individually or in combination is considered to be useful in the scope of the invention 'however' conventional chlorofluorocarbons or mixtures thereof may also be used as Propellants for Inventive Formulations It is well known in the art that the carrier and/or bulking agent is an inert material in which the active pharmaceutical ingredient and excipient (if present) are dispersed. When the formulation of the present invention utilizes HFA 227 as a propellant, it is unexpectedly found that the carrier is not necessary. Accordingly, a metered dose inhaler containing an aerosol suspension formulation for inhalation is disclosed, the aerosol suspension formulation for inhalation comprising: an effective amount of mometasone furoate; an effective amount of famot Alcohol fumarate and 1,1,1,2,3,3,3-heptafluoropropanone; wherein the ratio of mometasone furoate to faroterol fumarate is about 400 micrograms Momei It is about 12 micrograms of farnesol fumarate to about 5 micrograms of mometasone furoate to about 6 micrograms of famotote fumarate, of which mometasone furoate Velvet Coverage-11- This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm)

Binding

Line 1324934 A7 ________B7_ V. INSTRUCTION DESCRIPTION (9) (Flocculate) The farteol fumarate, and wherein the formulation is substantially free of carrier. The process for preparing the formulations of the present invention preferably utilizes HFA 227 or HFA 134a or a combination thereof in combination with mometasone furoate and famotote fumarate, and optionally a liquid excipient and, optionally, Surfactant. The excipient can promote the compatibility of the drug with the propellant and reduce the discharge pressure to an appropriate range, that is, about 2.76-5·52 χ 105 N/m 2 absolute pressure (4 〇 to 8 〇 (4), preferably 3.45 -4.83χ105 Newton/m 2 absolute pressure (5〇 to 7〇psi) The selected excipient should not be used with medicine, relatively non-toxic and need to have a vapor pressure of less than about 3.45\1〇5N / m2 absolute pressure (5〇1^) As used herein, 'medium chain fatty acid' represents an alkyl chain having a terminal of _c〇〇H group and having 6 to 12 carbon atoms, preferably 8 to 1 carbon atoms. "Short chain Fatty acid " represents an alkyl chain having a terminal -COOH group and having 4 to 8 carbon atoms. "Crush" - the word contains (: "(: 3 alcohols such as methanol, ethanol and isopropanol. Among them, preferred type The agent is: a propylene glycol diester of a medium chain fatty acid (purchased from Piswellia! ^ LiHuls America) under the trade name Migly〇l 840; a medium chain fatty acid triglyceride (purchased from Huh under the trade name Miglyol 812) ); pentafluorodimethylcyclobutane (available from EI DuPont de Nemours, Dallas, Wellington) under the trade name Vertrel 245; Pentafluorocyclobutane (purchased from Gent County, Florida) under the trade name pentafluorocyclobutane; polyethylene glycol (available from BASF from Paspa) under the trade name EG 4〇〇; mint Alcohol (available from International Corporation of Stanford, Connecticut), propylene glycol monolaurate (available from Eatford NY's Gattefosse) under the trade name Lauryl Glycerin; supplied under the trade name Tr-ajL5cut〇1-12 - This paper is again applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1324934 A7

: Diethylene glycol monoethyl ether (purchased from Gattef 〇SSe): Polyglycerol glycerol vinegar addition to the middle chain fatty acid (purchased from Gattefosse) under the trade name Lab Oil c 1219; alcohols such as ethanol, methanol and isopropyl Alcohol; eucalyptus oil (purchased from Pluess-Stauffer International); and mixtures thereof. Surfactants are often included in aerosol formulations to maintain a stable suspension of the drug and to lubricate the metering. The present invention ί = requires a surfactant to maintain stable dispersion (eg, immediately prior to use)

Stirring] 'Because the drug forms loose flocculation in the propellant and does not exhibit a tendency to S drop or impact. The HFA 227 maintains its flocculation suspension without disturbing the storage of the towel. Therefore, surfactants may be added as appropriate to reduce the surface and interfacial tension between the drug and the propellant. When the pharmaceutical, propellant and excipient form a suspension, the surfactant may or may not be required. When a pharmaceutical, propellant, and excipient forms a solution, it may or may not require a surfactant, depending in part on the solubility of the particular drug or excipient. The binding agent can be any suitable non-toxic compound that does not react with the drug and which substantially reduces the surface tension between the drug, excipient and propellant and/or acts as a valve lubricant. The preferred surfactant is: oleic acid supplied under the trade name oleic acid NF6321 (available from Henkel, Cincinnati, OH)

Emery Group); cetylpyridinium chloride salt (purchased from the power of Nishiki N丄 〇 〇 化学 chemistry); soy lecithin under the trade name Epikuron 200 (purchased from

Lucas Meyer Decatur, III) 'Polyoxyethylene (20) sorbitan monolaurate (available from Dalway Wellington 专业^ Professional Chemicals) under the trade name Tween 20; under the trade name Tween 60 Polyoxyethylene oxime (2 〇) sorbitan monostearate (available from ICI); 13-is available under the trade name Tween 80. This paper scale applies to the China Standard (CNS) A4 specification ( 210X 297 mm) 1324934 A7 _____ B7 V. INSTRUCTIONS (n) Polyoxyethylene (20) sorbitan monooleate (purchased from ICI); polyoxyethylene (1 〇) supplied under the trade name Brij 76 Aliphatic ether (available from ICI); polyoxymethylene (2) oleyl ether (available from ICI) under the trade name Brij 92; polyoxyethylene-polyoxypropylene provided under the trade name Tetr〇nic 150 R1 Ethylenediamine-labeled copolymer (purchased from BASF)' under the trade name piuronic L-92, Pluronic L-121 and

Polyoxypropylene-polyoxyethylene block copolymer (available from BASF) supplied by Pluronic F 68; castor oil ethoxylate supplied under the trade name Alkasurf CO-40 (purchased from Rh., Otano, Missouri, Canada) Ne.p〇ulenc). Since other drugs have a slight solubility in ethanol, there is a tendency for mometasone citrate to exhibit crystal growth in an ethanol-containing formulation. Formulation parameters that do not promote drug particle size growth are known. These parameters provide the advantage of minimizing the desired ethanol concentration, reducing the potential for unpleasant taste and making the composition more suitable for children and other patients with low alcohol tolerance. It is preferred to use a minimum amount of ethanol for the knowledge that the amount of impulse I is the adapter k for continuous and predictable delivery of the drug. This minimum amount is about 1% by weight of the total formulation, which results in a marginally acceptable drug delivery. The increased amount of ethanol generally improves the drug delivery characteristics. However, in order to avoid drug crystal growth in the formulation, it is better to limit the present fermentation concentration. . Experimental data shows that the weight ratio of mometasone to ethanol is important to avoid particle size increase. The active ingredient can be placed in a container containing the formulation as follows: the medicine is enclosed and the container can be filled with the pharmaceutical 'ethanol and surfactant' in a single or multiple steps, preferably in a single step. Similarly, a propellant or propellant mixture can be added to the vessel in the same or multiple steps. The suspension of the formulation of the present invention contains the constituents of the shuffling material. The floc is a particle that forms a structural lattice and is resistant to complete sedimentation.

丄 V. Description of invention (

A7 B7 agglomerate of particles. The number of lattices Jia's dispersing structure makes the aggregates easy to break and easily interfere with a small amount of agitation. #诅+, , The preparation of momethacin is suspended in the propellant. After a long time, the mometasone is loosened with _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The particles are easily dispersed by shaking or shaking the inhaler canister in the dose θ β . Unexpectedly, adding the method to the suspension of the suspension: brewing π 1 k Μ ., _ special alcohol does not change this performance. When the propellant is UFA, the farotropin is agglomerated with the mometasone in the suspension, and the mometasone and the faroterol are agglomerated with each other. When the pusher is HFA 134a, it is preferred that a swelling agent or carrier such as lactose is present in an amount of from about 0.05% to about 0.3% by weight to enhance drug delivery after inhaler actuation. (10) The main formulation of 'famotol, mometasone and lactose has a tendency to settle to the bottom of the tank, because HFA 134a has a lower density than HFA 227; therefore, it is better to shake the tank before driving the meter to form The suspension provides uniform drug delivery. Other bulking agents that can be used in the suspension of HFA 134a include, for example, mannitol, glucose, sucrose, and trehaisse. . The formulations of the present invention are prepared in accordance with procedures conventional in the art for making other aerosol compositions. Typically, all ingredients are mixed and introduced into the aerosol container except for the propellant. The container is then chilled to a temperature below the boiling point of the propellant and the desired amount of frozen propellant is added before the metering valve is placed over the container. Further, the container can be configured with a metering valve prior to filling in the propellant, and a desired amount of propellant can be introduced via the valve. The formulations of the present invention can be filled into an aerosol container using conventional filling techniques. Since HFA 227 and HFA 134a may be incompatible with all of the elastomeric compounds currently used in the aerosol valve assembly of the present invention, it may be necessary to replace other materials such as white buna rubber or to utilize excipients and, if appropriate, the interface tongue. · This paper scale applies to the Chinese National Standard (CMS) Μ Specifications (210X 297 mm)

Binding

Line 1324934 A7 B7

The agent can slow down the adverse effects of HFA 227 or HFA 134a on the valve into eight, 丄 1 mesh. The suspensions of the present invention are preferably prepared by pressure filling or cooling and filling procedures known in the art. Depending on the particular application, the container may be fed with an appropriate amount of the formulation for single or multiple doses - typically the 'container size' is determined by multiple doses: therefore, it is extremely important that the delivered formulation is administered to each substance. The above is uniform. example

For example, when the formulation is used for bronchodilation, the container is typically fed with a sufficient amount of formulation for 200 actuations. Suitable suspensions can also be partially screened by observing several physical properties of the formulation, i.e., particle agglutination rate 'aggregate size and particle emulsification/settling rate and compared to acceptable standards. This suitable solution can be screened/evaluated by measuring the solubility of the drug over the entire recommended storage temperature range.

For dose metered dose inhalers, the suspension may be particularly good in terms of efficiency and solubility considerations. It is well known to those skilled in the art to add one or more preservatives, buffers, antioxidants, sweeteners and/or flavoring agents or other taste masking agents depending on the formulation characteristics. The dose valve delivery volume is provided in the range of from about 25 to about 1 microliter per actuation, and the desired drug mass in the dose used to treat a particular condition typically drives from about 10 to about 500 micrograms per valve. This combination of two factors limits the point within the aforementioned ethanol parameters that direct the intended formulation. The determination of this amount is well known to those skilled in the art. In formulations of the invention suitable for treating lower respiratory system disorders such as asthma, at least a substantial portion of the drug is present as suspended particles having a particle size such as a maximum size of from about 5 to about 1 micron. Applicable to the treatment of upper respiratory tract disorders. Rhino -16-1324934 A7 B7 V. INSTRUCTION DESCRIPTION (Μ) In the formulation of inflammation, the drug particles of the peak can be allowed, but it is better to maintain the aforementioned size range. When the active compound forms a suspension, the particle size needs to be fairly uniform, and substantially all of the particles are preferably in the range of about 0. 25 microns, preferably 0.5 to 10 microns, more preferably 1 to 5 microns. Particles larger than 25 micron may remain in the oropharyngeal cavity, and particles less than about 0.5 micron are preferably not used because they are more prone to emanate and therefore cannot reach the lungs of the patient. Also within the scope of the invention are methods of treating airway diseases which may be treated with effective amounts of mometasone furoate and faroterol fumarate as described in Examples 3, 4 and 5 below. The medicament may be administered once or twice daily according to the dosages described in Examples 3, 4 and 5 below. Another object of the invention comprises a novel formulation comprising two drug substance powders mometasole citrate and faroterol fumarate as a third powder surfactant such as egg yolk known in the art. A dispersion system of a well-mixed ternary blend of stearic acid, palmitic acid, magnesium stearate, magnesium palmitate, magnesium laurate, and other suitable dry powder blend surfactants. The dry blend can be mixed, for example, in a Turbula mixer T2C for about 5 minutes, or mixed to the time known in the art to achieve a uniform blend of powders. The dispersion system is metered into each inhaler tank by powder filling equipment, such as 15 ml of aluminum Teflon coating (FPT-fluorinated ethylene copolymer) or other polymer by Autodose Powdernium- One Too Many System. In the pot on foot. The canister can then be inserted into a 63 microliter valve and filled with HFA-227 or HFA-134a propellant using a propellant filling device, for example, Pamasol Model Ρ 2008/012^\. The tank filled with the suspension product is then ac acoustically vibrated by a vibrator such as a Branson 5210 vibrator for about 5 minutes, which is known as the Chinese National Standard (CNS) A4 specification (210 X 297 mm).

Binding

1324934 A7 B7 V. INSTRUCTIONS (15) This skill is known to the public. These particular formulations produce a combination of two drug substances, MDI, which exhibits sustained drug content uniformity (DCU) without the use of additional excipients and/or additives. The use of such a dry 2-step filling procedure eliminates the possibility of crystal growth of the active ingredient during the filling process and does ensure a constant particle size distribution in the product that is filled during the beginning, intermediate and final filling process. This formulation and the filling process ensure that the granules are properly dispersed in the suspension medium HFA-227 without crystal growth, agglomeration and uniform drug content uniformity during delivery. Some objects of the invention are further described in the following examples. In the examples, "% " means weight percent unless otherwise stated. The following examples further describe the invention. The following dry powder blend samples were prepared. Example 1 Table 1. Mometasone citrate (91%), Dry powder blend of farotropol fumarate (9%) and lecithin (0.1%, 0.01% and 0.02%) · mometasone furoate (mg) farnesol fumarate (mg) Lecithin (mg) Total weight of the blend (mg) Weight per can (mg) 616.0 61.70 0.686 678.4 13.57 621.0 62.00 0.070 683.1 13.66 621.0 61.80 0.144 682.9 13.66 \All weights in the ternary blend w/w Benchmark

Line As shown, the weight ratio of mometasone furoate to faroterol fumarate is approximately 10 to 1. For the preparation, directly mix the above -18- in the Turbula mixer. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 1324934 A7 B7 5. Inventive Note (16) The amount of mometasone The dry powder blend of citrate, faroterol fumarate and lecithin was mixed for about 5 minutes. Subsequently, the metered mixture such as equipment was filled into a 15 ml tank using Autodose Powdernium powder. Then, insert a 63 μl valve and add propellant to approximately 10 g/can. Then the sound is shaken for 5 minutes. Example 2 Table 2. Mometasone decanoate, famotote fumarate, lecithin and HFA-227MDI formulation blend ^ mometasone citrate (%) famotol fuma Acid salt (%) Lecithin (%) HFA-227 (°/〇) 0.1 0.01 0.01 99.88 0.1 0.01 0.001 99.89 0.1 0.01 0.002 99.89 # : All weights are given in the finished product w/w benchmark. Table 2 describes the various amounts of activity. The ingredients and surfactants were combined with HFA-227 in a completed metered dose inhaler canister. Some other objects of the invention are further illustrated in the following examples. In the examples, "%" means the percentage by weight unless otherwise stated. The following examples further describe the invention. Examples 3, 4 and 5 provide examples of varying amounts of various ingredients of the formulations of the present invention. -19- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Binding

Line 1324934

Formulation prototype (drug momeitan pine famot 5f oleic acid ethanol HFA-227: drug) ratio hydrochloride (%) (%) (%) (%) A (100 β%·. ^ yCZg) 0.112 --------- — 0.009 0.001 2.378 97.5 B (50 # g:6 /zg) 0.056 0.007 0 2.437 97.5 C (100 #g:8 仁g) 0.112 0.009 0.011 2.368 97 5 D (200 βξ,.η fig) 0.224 .0.014 0.011 2.251 97.5 E (100 ^g: 8 μξ) 0.112 0.009 0 2.379 97.5 ¥(50 β :6 β) 0.056 0.007 0 001 2 436 97 5 G(50 ^g: 6 0.056 0.007 0.011 2.426 97.5 H(5〇.^g:6 μ.%) 0.056 0.007 0.011 1.5 98.426 1(50 /zg:6 //g) 0.056 0.007 0.011 1.75 98.176 J (50 /zg:6 βξ) 0.056 0.007 0.0 1.5 98.437 K(50 ^g:6 /ig) 0.056 0.007 0.0 1.75 98.187 L (200 β g: 12 β g) 0.224 0.014 0.011 1.5 98.251 M(200 仁g:12 私g) 0.224 0.014 0.011 1.75 98.001- N (200 β% Λ 2β%) 0.224 0.014 0.0 1.5 98.262 0(200/zgl2 //g) 0.224 0.014 0.0 1.75 98.012 -20- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1324934 A7 B7 V. INSTRUCTIONS (18) Example 4 Formulation prototype (drug: Proportion of mometasone citrate (%) famotol fumarate (%) oleic acid (%) ethanol (%) HFA-134a (%) A (100 //g: 8 ^g) 0.112 0.009 0,001 2.378 97.5 B (50 #g:6 from g) 0.056 0.007 0 2.437 97.5 C (100 //g:8 /zg) 0.112 0.009 0.011 2.368 97.5 D (200 "g: 12 eg) 0.224 0.014 0.011 2.251 97.5 E(100 /ig:8 /zg) 0.112 0.009 0 2.379 97.5 F (50 ^:6 //) 0.056 0.007 0.001 2.436 97.5 G(50 #g:6 私g) 0.056 0.007 0.011 2.426 97.5 H(50 ^g :6 fig) 0.056 0.007 0.011 1.5 98.426 1(50 /2g:6 eg) 0.056 0.007 0.011 1.75 98.176 J (50 /zg:6 /zg) 0.056 0.007 0.0 1.5 98.437 K(50 /ig:6 ^g) 0.056 0.007 0.0 1.75 98.187 L(200 /zg:12 /zg) 0.224 0.014 0.011 1.5 98.251 MP(200 #g:12仁g) 0.224 0.014 0.011 1.75 98.001 N (200 /zg:12/ig) 0.224 0.014 0.0 1.5 98.262 0 ( 200 ^g: 12 //g) 0.224 0.014 0.0 1.75 98.012 -21- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1324934 A7 B7 V. Invention description (19) Example 5 Formulation prototype (drug: drug) ratio of mometasone citrate (%: Famotetan fumarate (%) Oleic acid (%) Ethanol (%) HFA-227/ HFA-134a (50:50) (%) A(100 #g:8 eg) 0.112 0.009 0.001 2.378 97.5 B (50 ^g:6 /ig) 0.056 0.007 0 2.437 97.5 C (100 /zg:8 /zg) .0.112 0.009 Read 1 2.368 97.5 D (200 ^g:12 /zg) 0.224 0.014 0.011 2.251 97.5 E (100 /zg:8 /ig) 0.112 0.009 0 2.379 97.5 F (50 β :6 β) 0.056 0.007 0.001 2.436 97.5 G(50 //g:6 ^g) 0.056 0.007 0.011 2.426 97.5 H (50 ^g:6 /zg ) 0.056 0.007 0.011 1.5 98.426 1(50 yg:6 # g) 0.056 0.007 0.011 1.75 98.176 J (50 /ig:6 /zg) 0.056 0.007 0.0 1.5 98.437 K(50 /zg:6 /zg) 0.056 0.007 0.0 1.75 98.187 L(200 /zg:12 β%) 0.224 0.014 0.011 1.5 98.251 M (200 β%Λ2 //g) 0.224 0.014 0.011 1.75 98.001 N (200 ^g:12/zg) 0.224 0.014 0.0 1.5 98.262 0 (200 "g : 12 #g) 0.224 0.014 0.0 1.75 98.012 The formulations of the invention were further analyzed as described in Examples 6 and 7 using an Andersen cascade bumper. The Andersen cascade bumper is widely used to measure the particle size distribution of particles dominated by gases, especially pharmaceutical aerosols. When the backing filter is used after the final collision stage, the 8-stage Andersen Crasher will sample -22- this paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1324934 A7 B7 V. Description of the invention ( 20) divided into 9 size intervals. In Figures 1 to 4, this corresponds to a stage of particles having a particle size of less than 10 μm to a particle size of 0.65 to 0.43 μm of stage 8, and a final stage corresponding to a filter of particles smaller than 0.43 μm. The particle size measured in the "throat" is equivalent to the entrance of the bumper. The fine particle fraction is defined as the percentage of particles with a particle size of less than 4.7 microns. Fine particle dosing is defined as less than 4.7 microns per dose in each drive. The microgram/injection is the total amount of drug product exiting the metered dose inhaler after actuation. The particle size distribution of the dose of the formulation is measured using an Andersen cascade bumper as is well known to the skilled artisan. Example 6 Formoterol /Morme Pine 6/50 μg/Drive Combination Inhaler Andersen Cascade Bumper Data - HFA 227, No Expansion System Momimezepine Starts 1 Month 3 Months 4 Months 4C/40C 40C/75% 4C/40C 25C/60% 40C/75% Fine particle fraction % 36.5 16.4 25.3 9.8 30.4 18.6 Fine particle dose (μg/spray) 19.7 9.2 13.9 5.3 16.1 10.4 MMAD (micron) 3.7 5.0 4.1 6.3 4.2 4.6 Microgram/spray (dosage measurement) 62.9 62.6 62.4 60.5 61.5 63.3 -23- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1324934 A7 B7 V. Description of invention (21) Famo phase F alcohol Fumarate starting V Μ 3 months 4 months 4C/40C 40C/75% 4C/40C 25C/60% 40C/75% Fine particle fraction% 46.3 39.0 41.1 35.2 47.3 40.1 Fine particle dose (μg/jet) 2.6 2.2 2.4 1.9 2.6 2.2 MMAD (micron) 3.2 3.3 3.2 3.3 3.2 3.4 μg/spray (dosing) 6.6 6.3 6.6 6.3 6.5 6.5 6 micrograms of famotote fumarate and 50 micrograms of mometasone in a metered dose inhaler Salts and formulations using HFA 227 without a bulking agent or carrier were analyzed using an Andersen cascaded bumper to analyze the amount of active pharmaceutical ingredient over time and the particle size of the active ingredient leaving the inhaler. As shown, mometasone and The fine particle dose of the farteol over time and after the temperature cycling of the conditions is maintained within acceptable limits (at 4 months, the mometasone is 19.7 to 10.4 and the faroterol is 2.6 to 2.2) The time-dose dosing of the two active ingredients is also maintained within acceptable limits (compared with 62.9 to 63.3 for mometasone and 6.6 to 6.5 for faroterol at +month). The particle size distribution of mometasone-salt and faroterol as described in Figures 1 and 2. This data shows an improved and acceptable drug delivery of the two active ingredients. Although the fine particle size fraction of mometasone citrate seems to decrease by almost half, this is attributed to the roughness of the mometasone citrate grade used. There is a silver between the product quality and the corresponding range of drug substances suspended in the product. -24- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm)

Binding

1324934 A7 B7 V. INSTRUCTIONS (22) RELATIONSHIP. A drug substance having a high proportion of large crystals greater than 5 to 10 microns is determined to produce a product having a particle size distribution aerodynamically outside the range of typical effective local lung administration. Products containing relatively crude drug products also exhibit particle growth that is unacceptable over time and temperature. The finer particle size distribution of mometasone furoate improves the fine fraction of the formulation leaving the inhaler when the metered dose inhaler is driven. Indeed, the percentage of fine particle size after the cycle of the mometasone used in the above examples at -10 ° C and 40 ° C for 2 weeks was changed by about 50%. However, the use of mometasone oxime alone, similar to MDI but with a finer grade of mometasone, shows only about 15% or less of the fine particle size under the same cycling conditions. This results in an increase in the fine particle fraction of mometasone and thus improved drug delivery of mometasone. Thus, it has been found that the use of a finer particle size grade of the drug substance produces a product having suspended drug particles that do not exhibit particle growth over time and temperature. The aerodynamic particle size distribution is within the range of typical effective local lung administration, i.e., more than 50% of the particles are less than 4.7 microns. It also shows no significant grain growth over time and temperature. In the case of oral MDI containing mometasone citrate, the following provides an example of an acceptable product profile using a 100 gram/drive strength of the Andersen cascade bumper and 1-liter inlet. It should be noted that this data is based on the two actuations of the metered dose inhaler. -25- This paper scale applies to China National Standard Rate (CNS) A4 specification (210 X 297 mm) A7 B7, invention description (23) Table 1 Andersen cascading collision stage deposited on the plate of the amount of particles 1 group - entrance + Stage 〇 8-22 μg 2 group - Stage 1 + Stage 2 12-21 μg 3 group - Stage 3 + Stage 4 122-140 Microgram 4 group - Stage 5 · Filter 22-41 μg 1324934 1 Group fine particle percentage range About 49% to about 9 8%. The percentage of fine particles in the two groups ranges from about 7 3% to about 94%. The percentage of fine particles of Stage 3 to Filter and 4,) preferably ranges from about 55% to about 85 Å/Torr, wherein fine particle granulation is less than about 4.7 microns, preferably 65% to 80, based on the above table data. % 'or about 80%' or about 85% and about 81% to about 89%. Finally, the percentage of fine particles in the four groups ranges from about 13 4% to about 18 3%. The size of the suspended mometasone citrate contained in the pharmaceutical product can be controlled in several ways. The drug substance can be more effectively ground prior to manufacture of the product batch. This solid contains a reduced micronized feed rate, the use of centrifugation to remove larger particles and an increase in the number of cycles, the material being fed into the micronizer such as double micronization. In addition, the drug substance can be used, for example, before the product batch is manufactured. The supercritical adult technique sprays to produce uniform small particles of drug material. Further, the manufacturing method can be modified, for example, by lowering the batch manufacturing temperature, reducing the amount of alcohol used to prepare the pharmaceutical concentrate, or reducing the homogenization time. Finally, other processes known in the art for controlling the particle size of the drug substance can be used, such as the use of surfactants or other particle size growth barriers. -26- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm)

Binding

Line 1324934 A7 B7 V. INSTRUCTIONS (24) Example 7 Andersen Cascade Crusher Data for Fatot Alcohol/Memomethadone 6/50 μg/Drive Combination Inhaler - HFA 134a, Low Expansion Agent System Momedis Pine Citrate 1 month 3 months 4 months 4C/40C 40C/75% 4C/40C 25C/60% 40C/75% Fine particle fraction % 25.7 20.1 20.1 20.0 22.6 17.7 Fine particle dose (μg/jet) 13.6 10.6 10.1 10.0 11.4 8.8 MMAD (micron) 3.9 4.3 4.3 4.6 4.3 4.5 μg/spray (dosing) 64.1 65.0 62.2 62.6 62.1 63.7 Famote alcohol fumarate initially 1 month 3 months 4 months 4C/40C 40C/75% 4C/40C 25C/60% 40C/75% Fine fraction. /〇42.5 38.0 41.3 40.2 43.6 40.3 Fine particle dose (micrograms/laser) 2.4 2.0 2.1 2.2 2.3 2.1 MMAD (micron) 2.9 3.1 2.9 3.2 3.0 3.1 microgram/spray (dosing) 6.9 6.5 6.3 6.8 6.7 6.6 Inhalation at dose The product contains 6 kefamotol fumarate and 50 micrograms of mometasone citrate using HFA 134a and lactose as the most bulking agent. -27- This paper scale is the common Chinese standard (CNS) A4 size (210X297 mm) 1324934 A7 B7 V. Description of the invention (25 The formulation uses the Andersen Cascade Crusher to analyze the time-dependent amount of the active pharmaceutical ingredient leaving the inhaler and the time-dependent particle size of the active ingredient. The dose of fine particles of Mowusong and *Motol and the temperature cycle is maintained within the repairable degree (13 to 8 for mometasone) and 2.4 to 2. for Famo (four). D. In addition, the doses that are actually delivered are also within acceptable limits over time (for mometasone to ... to (1) and for faroterol to (1) to 6.6). These data pairs should be in Figure 3 and 4-methodol and momethacin H knife cloth for both mometasone and famotol The particle fraction is maintained within acceptable limits. The data solutions show improved drug delivery of the two active agents via a dose sf inhaler. Furthermore, as described in Example 6, only a similar MDI using the momoline-like salt is used. However, the finer grade of mometasone salt indicates that the fine particle size changes only about 15% or less under the same cycle conditions. This leads to an increase in the fine particle fraction of the mometasone, and thus the improved mometasone Crude drug delivery.Example 8 The degradation products of the formulations of the invention were analyzed at 40 ° C and 75% relative humidity for 4 months. -28- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1324934 A7 B7 V. INSTRUCTIONS (26) Impurity HFA277, non-expanded HFA 134a, low-expansion farteol degradation product-2566 0.10 0.21 Total farteol is known to degrade 0.10 0.09 w/o SCH-2566 Total method Unknown alcohol degradation 0.13 0.38 Total farmore alcohol degradation w/o 0.23 0.47 XSCH-2566 Compound E 0.06 0.23 Total momethacin known degradation 0 0 w/o compound E Total mometasone unknown degradation 0.13 0.13 Total Mo It is degraded by 0 .19 0.35 Total Related Substances 0.51 1.03 As shown, the non-expanded formulation containing HFA 277 has substantially less degradation products than the bulk of the expansion formulation containing HFA 134a. Specifically, the HFA 227 formulation contains less than 0.1% degradation product (referred to as Compound E), which is an epoxide-type degradant associated with mometasone. Formulations containing mometasone furoate containing less than 0.1% of Compound E meet the FDA specifications for the inhalable formulation containing mometasone furoate in the presence of this particular compound. -29- This paper is sized according to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1324934 A7 B7 V. Description of invention (27) Example 9 Famotetan/mometazin 6/50 μg/ Drug content uniformity of the driving combination inhaler - HFA 227, no expansion agent system _ Momeiita pine sulphate 1 month 4C/40C 40C/75% total net average micro gram ten '54.7 55.6 54.9 relative standard deviation 11.5 9.6 6.1 Valentate fumarate for the first month _ 4C/40C 40C/75% total average microgram 1 shot 5.7 5.5 5.7 relative standard deviation 11.6 10.4 6.6 Example 10 faroterol / mometasone 6 / 50 micrograms / Drive combination inhaler drug content uniformity - HFA 134a, also volume expander system mometasone citrate 1 month 4C / 40C 40C / 75% total average microgram / injection 59.1 55.7 57.0 relative standard deviation 17.9 10.9 19.6 -30- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1324934 A7 B7 V. Description of invention (28) Fatotrol fumarate for the first month _ 4C/40C 40C /75% total average microgram/jet 6.2 5.6 6.0 relative standard deviation 17.3 11.2 26.1 entire The drug content uniformity (DCU) of the inhaler was measured over the life of the 120-dose MDI to investigate whether the active ingredient was administered continuously throughout the life of the product. Each formulation (HFA 227 or HFA 134a) analyzed 5 cans and each canister delivered 120 times to drive the drug and under the drive of change, ie the number of 11, 12, 13, 14, (start) 59, 60, 61, § 2 (Intermediate phase) and 117, 118, 119 and 120. (final), the amount of active agent per actuation of the inhaler was measured. The averaging was determined for the initial, intermediate, and final drive, and the entire average was determined and described in Examples 9 and 10 above. Although the HFA 227 formulation has a relatively low relative standard deviation of the amount of drug leaving during the life of the MDI, both formulations produce acceptable results for the uniformity of drug content over time. The various specific examples of the invention described above are illustrative of the various objects of the invention and are not intended to be limited or limited. Many modifications and changes are undoubtedly known to those skilled in the art. It is intended that the scope of the invention be defined only by the scope of the appended claims. -31- This paper is again applicable to China National Standard (CNS). A4 specification (210X297 mm)

Claims (1)

*month, 4, month j wood K9 1324934 EH fiber more) original 苐〇9Π1925 专利 专利 patent application sentence Chinese application patent range replacement 4 Apply for a patent Fan Park L. Dosage metered inhaler containing an aerosol suspension formulation for inhalation, the aerosol suspension formulation for inhalation comprising: an effective amount of mometasone furoate; an effective amount of faroterol fumaric acid Salt bismuth and 1,1,1,2,3,3,3·heptafluoropropane; wherein the ratio of the mometasone citrate to faroterol fumarate is about 4 〇〇 microgram of mometasone The acid salt is about 12 micrograms of famotote fumarate to about 5 micrograms of mometasone saccharate to about 6 micrograms of famotote fumarate, wherein the famotote fumarate is The mometasone furoate flocculent coating, and the intermediate formulation thereof, are substantially free of carriers. 2. A metered dose inhaler containing an aerosol suspension formulation for inhalation, as in the scope of the patent application, in addition to a surfactant. 3. A dosing metered-dose inhaler containing an aerosol suspension formulation for inhalation, in the scope of the patent application, wherein mometasone is present in an amount of about 5 μg and the presence of farotropin fumarate The amount is about 6 micrograms. 4. A metered dose inhaler containing an aerosol suspension formulation for inhalation as claimed in paragraph 1 of the patent, wherein mometasone is present in an amount of about 1000 micrograms and farotropin fumarate It is present in an amount of about 6 micrograms. 5. A metered dose inhaler containing an aerosol suspension formulation for inhalation as claimed in claim 1, wherein mometasone is present in an amount of about 5 micrograms and the presence of farotropin fumarate The amount is about 8 micrograms. 6. A metered dose inhaler containing an aerosol suspension formulation for inhalation as claimed in claim 1, wherein the mometasone is present in an amount of about 100 micrograms and the amount of famotote fumarate present About 8 micrograms. 7. If the aerosol suspension containing inhalation is included in the scope of the patent application, O:\79\79883-950411 DOC\ 5 t paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1324934 ABCD VI. Scope of application for a metered dose inhaler wherein mometasone furoate is present in an amount of about 200 micrograms of cofodol fumarate in an amount of about 12 micrograms. 8. If you apply for a patent scope! A metered dose inhaler comprising an aerosol suspension formulation for inhalation wherein the mometasone is present in an amount of about 400 micrograms and the farnesol fumarate is present in an amount of about 12 micrograms. 9. Use of an aerosol suspension formulation according to the scope of the patent application </RTI> for the preparation of a medicament for the treatment of respiratory allergies and inflammatory reactions&apos; wherein the medicament is for inhalation. 10. A method for producing an aerosol suspension formulation for inhalation, wherein the inhaled gas gluten suspension formulation comprises: an effective amount of momernose citrate; an effective amount of famotol fulvate And the 1'1,1,2,3,3,3-heptafluoropropane; wherein the ratio of the mometasone furoate to the faroterol fumarate is about 4 〇〇 microgram Momei The pine strontium salt is about 12 micrograms of famotote fumarate to about 5 gram micrograms of mometasone citrate to about 6 micrograms of famotote fumarate, of which is the farotropol fumarate. The salt is coated in a flocculent form of the mometasone citrate in the aerosol suspension formulation, and the intermediate formulation thereof does not contain a swelling agent; the method comprises the steps of: a) micronizing mometasone citrate a dry powder blend of salt and faroterol fumarate is mixed with a dry powder surfactant to form a homogeneous mixture; b) the mixture is filled into a metered dose inhaler tank. c) covered with a metering valve roll The tank; and d) the tank is filled with a non-chlorofluorocarbon propellant. O:\79\79883-9504 M.DOC\ 5 - 2 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm). 6. The product prepared by the method of applying for patent garden. 'The dry powder interface is live palmitic acid, magnesium stearate, palm sputum. The method is as described in the patent application. The method of claim 1 is selected from the group consisting of lecithin. a group consisting of stearic acid, magnesium sulphate and magnesium laurate containing a dose of aerosol suspension for inhalation. Inhalation of aerosol suspension formulation includes: an effective amount of Momei It is a bismuth citrate; an effective amount of a surfactant of farotropin fumarate·dry powder, and a seven-a-propyl propyl sulphonate; wherein the mometasone citrate to the famotol fumarate The ratio is about 4 〇〇 microgram mometasone citrate to about! 2 micrograms of famotote fumarate to about 5 〇 microgram of mometasone citrate to about 6 micrograms of famotote fumarate, wherein the farotropol fumarate is momethanone The acid salt floc coating wherein the formulation has no additional excipient and wherein the dose metered inhaler has a uniform drug content at the dose that is driven when the metered dose inhaler is driven. 14. A dose inhaler comprising an aerosol suspension formulation for inhalation, the aerosol suspension formulation for inhalation comprising: an effective amount of mometasone furoate; an effective amount of famotol Fumarate; and 1,1,1,2,3,3'3-heptafluoropropane; wherein the ratio of the mometasone furoate to the faroterol fumarate is about 4 〇〇 microgram Momei It is about 1 2 micrograms of farnesol fumarate to about 5 micrograms of mometasone furoate to about 6 micrograms of famotol fumarate, of which is a famotol The acid salt is coated in a flocculent form with mometasone decanoate, and wherein the formulation contains less than 0.1% of the epoxide degradation product of mometasone citrate. 15. Dosimetric inhalation of a formulation containing an aerosol suspension for inhalation 0:\79\79883.9504ΠΌ〇α 5 A8 B8 C8 D8 VI. Application for a patent, the aerosol suspension for inhalation The composition comprises: an effective amount of mometasone; an effective amount of faroterol fumarate; and 1'1,1'2,3,3,3-heptafluoropropane; wherein the mometasone The ratio of the acid salt to the farnesol oxime acid salt is about 40 〇 microgram of mometasone citrate to about 12 micrograms of famotote fumarate to about 5 〇 microgram of mometasone citrate For about 6 micrograms of famotote fumarate, wherein the farnesol fumarate is flocculated with mometasone citrate, wherein the percentage of fine particles dispensed by the metered dose inhaler is about 5 From 5% to about 85%, and wherein the fine particles have a particle size of less than about 4.7 microns. 16. The dosimeter inhaler comprising an aerosol suspension formulation for inhalation according to claim 15 wherein the percentage of fine particles dispensed by the dose metering inhaler is from about 65% to about 8%, And wherein the fine particles have a particle size of less than about 4 · 7 microns. O:\79\79883-950411 .DOQ 5 This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm)